A newly developed infrared ion spectroscopy (IRIS) platform offers robust, high-resolution structure elucidation of metabolites and isomers – providing a complement to mass spectrometry in pharmaceutical analysis. The system, now implemented in an industrial laboratory at Johnson & Johnson, integrates a high-repetition-rate infrared laser with a quadrupole ion trap mass spectrometer, achieving high reproducibility without daily recalibration or optical tuning.
Infrared ion spectroscopy couples the selectivity of MS with vibrational fingerprinting via IR absorption. When the IR laser is tuned to specific vibrational modes of trapped ions, resonant energy absorption induces fragmentation – a process known as infrared multiple-photon dissociation (IRMPD). By monitoring the dissociation yield across a scanned wavelength range, researchers generate IR spectra that help distinguish isomers and localize structural modifications.
The new platform uses a 30 kHz, 2 W optical parametric oscillator laser system, achieving high IRMPD yields even for ions traditionally difficult to dissociate. Benchmarking experiments with protonated tryptophan showed complete precursor ion depletion and linear scaling of IR signal with irradiation time and helium pressure. Repeat measurements over eight months demonstrated excellent spectral reproducibility without instrument adjustment, underscoring the system’s stability.
The researchers also demonstrated enhanced performance for challenging analytes. For example, deprotonated para-coumaric acid – previously resistant to dissociation – showed marked spectral improvements, allowing clear identification of isomeric forms via diagnostic OH stretch vibrations. These capabilities enable isomer differentiation without chemical derivatization or full analyte purification.
To test real-world utility, the team applied the system to determine glucuronidation and oxidation sites in drug metabolites. Using density functional theory (DFT) and Born–Oppenheimer molecular dynamics (BOMD) calculations to predict vibrational spectra, they accurately assigned the site of glucuronidation in a serotonin metabolite and distinguished between 10-hydroxy and N-oxide forms of amitriptyline.
While currently limited to the 3 μm spectral window, the authors suggest that future high-power tabletop lasers targeting the fingerprint region (5–20 μm) could further expand IRIS capabilities.
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